Use of an ang-(1-7) receptor agonist in acute lung injury

ABSTRACT

The present invention refers to a peptidic or non-peptidic angiotensin(1-7) (Ang-(1-7)) receptor agonist, preferably a Mas receptor agonist, for the prevention and/or treatment of acute lung injury, preferably acute respiratory distress syndrome.

CROSS-REFERENCE TO RELATED APPLICATIONS

This present invention is a continuation of U.S. patent application Ser. No. 13/063,685, filed May 5, 2011, which is a national phase entry of International Application No. PCT/EP2009/006619, filed Sep. 11, 2009, and refers to a peptidic or non-peptidic angiotensin-(1-7) (Ang-(1-7)) receptor agonist, preferably a Mas receptor agonist, for the prevention and/or treatment of acute lung injury, preferably acute respiratory distress syndrome, the entire contents of both of which are incorporated herein by reference.

The present invention refers to a peptidic or non-peptidic angiotensin-(1-7) (Ang-(1-7)) receptor agonist, preferably a Mas receptor agonist, for the prevention and/or treatment of acute lung injury, preferably acute respiratory distress syndrome.

SEQUENCE LISTING

In accordance with 37 C.F.R. §1.52(e)(5), a Sequence Listing in the form of a text file (entitled “Sequence_Listing,” created on Oct. 11, 2013 and 3 KB in size) is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

With age-adjusted incidences of 86.2 per 100,000 person-years and overall mortality rates of ˜43%, acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS), remain a major cause of death in intensive care (1,2). The pathological hallmarks of the disease comprise diffuse alveolo-capillary injury and an increased lung permeability associated with a strong inflammatory response (3,4). These changes underlie the clinical presentation which is characterized by an acute onset, severe hypoxemia and a proteinaceous lung oedema. Despite a multitude of large multi-centric clinical trials to explore the potential of various therapeutic strategies including the use of glucocorticoids, ketoconazole, lisofylline, alprostadil, inhaled NO or supplemented surfactant (5-7), no therapeutic pharmacological intervention could so far improve the clinical outcome of ALI/ARDS. So far, the only evident improvement for the survival of ARDS patients has been achieved by the implementation of minimal invasive ventilation strategies with low tidal volumes as compared to the previously used high tidal volumes (8).

In a recent experimental study, Imai and co-workers could demonstrate that angiotensin converting enzyme 2 (ACE2), which converts Ang II to Ang-(1-7) by cleavage of one amino acid, protects mice from severe acute lung injury induced by acid aspiration or sepsis (9). The authors attributed this finding to the fact that ACE2 will decrease Ang II concentration and thus, reduce the activation of the Ang II type I receptor (AT1). This notion has triggered a series of studies demonstrating the effectiveness of AT1 receptor blockers or ACE inhibitors for the treatment of various forms of experimental acute lung injury (10-13).

Importantly however, the cleavage product of Ang II by ACE2, Ang-(1-7), is not an inert waste product of the angiotensin-pathway, but may exert active biological functions. Ang-(1-7) binds to the G protein-coupled receptor Mas (14) which appears to be a physiological antagonist of the AT1a receptor (15), and potentially to other receptors. Binding of Ang-(1-7) to its receptor(s) may thus contribute critically to the previously demonstrated beneficial effects of interventions in the angiotensin pathway on the pathology of ALI/ARDS.

The U.S. Pat. No. 6,235,766 refers to non-peptidic agonists of Ang-(1-7) receptors, and particularly discloses 1-(p-thienylbenzyl)imidazoles having a marked action on Ang-(1-7) receptors and mimicking the biological action of the effector hormone Ang-(1-7).

The international patent application WO 2006/128266 refers to the interaction between the Mas receptor and Ang-(1-7) or its analogues in the context of controlling the functions of the reproductive system.

The international patent application WO 2007/000036 refers to the use of peptidic or non-peptidic Mas receptor agonists and antagonists as apoptotic activity modulators.

The international patent application WO 2007/121546 refers to the use of peptidic or non-peptidic Mas receptor agonists for modulating metabolic activities related to the clinical manifestation of the metabolic syndrome or its complications.

We speculated that Ang-(1-7) or related agonists may represent a new and promising strategy for the treatment of ALI/ARDS. Thus, the object of the present invention is to provide means and methods for a pharmacological intervention in the patho-physiologic events underlying ALI/ARDS.

SUMMARY OF THE INVENTION

The object of the present invention is solved by an Ang-(1-7) receptor agonist for use in the prevention and/or treatment of an acute lung injury in a subject.

The object of the present invention is solved by a method for the prevention and/or treatment of an acute lung injury in a subject using an Ang-(1-7) receptor agonist.

The object of the present invention is further solved by a use of an Ang-(1-7) receptor agonist for the preparation of a pharmaceutical composition for the prevention and/or treatment of an acute lung injury in a subject.

The object of the present invention is further solved by a method of prevention and/or treatment of an acute lung injury by administering an Ang-(1-7) receptor agonist to a subject.

In one embodiment, the Ang-(1-7) receptor agonist is a Mas receptor agonist. In one embodiment, the Ang-(1-7) receptor agonist interacts with a Mas receptor or a receptor associated with a Mas receptor.

In one embodiment, the Ang-(1-7) receptor agonist stimulates a receptor that physically interacts with a Mas receptor.

In one embodiment, the Ang-(1-7) receptor agonist stimulates a receptor that shares pharmacological similarities with a Mas receptor.

In one embodiment, the Ang-(1-7) receptor agonist is an Ang II metabolite sharing structural similarities with the Ang-(1-7) peptide.

In one embodiment, the receptor agonist is a peptidic or non-peptidic agonist. In one embodiment, the peptidic agonist is an exogenous or endogenous Ang-(1-7) peptide comprising an amino acid sequence Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-Pro⁷ according to SEQ ID NO: 1 or is a derivative or analogue thereof.

In one embodiment, the peptidic agonist is a derivative or analogue of the Ang-(1-7) peptide, the derivative or analogue comprising an amino acid exchange, deletion or insertion. Preferably, the derivative or analogue has conserved or better agonistic properties.

In one embodiment, the peptidic agonist is a derivative or analogue of the Ang-(1-7) peptide, the derivative or analogue comprising an amino acid sequence Asp¹-Arg²-Val³-Ser⁴-Ile⁵-His⁶-Pro⁷ according to SEQ ID NO: 2, Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-Cys⁷ according to SEQ ID NO: 3 or Asp¹-Arg²-Val³-Ser⁴-Ile⁵-His⁶-Cys⁷ according to SEQ ID NO: 4.

In one embodiment, the peptidic agonist is a peptide comprising an amino acid sequence according to SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 4.

In one embodiment, the peptidic agonist is an exogenous or endogenous NorLeu3-Ang-(1-7) peptide comprising an amino acid sequence Asp¹-Arg²-NorLeu³-Tyr⁴-Ile⁵-His⁶-Pro⁷ according to SEQ ID NO: 5 or is a derivative or analogue thereof.

In one embodiment, the peptidic agonist is an exogenous or endogenous Ang IV peptide comprising an amino acid sequence Val¹-Tyr²-Ile³-His⁴-Pro⁵-Phe⁶ according to SEQ ID NO: 6 or is a derivative or analogue thereof.

In one embodiment, the peptidic agonist is an exogenous or endogenous Ang III peptide comprising an amino acid sequence Arg¹-Val²-Tyr³-Ile⁴-His⁵-Pro⁶-Phe⁷ according to SEQ ID NO: 7 or is a derivative or analogue thereof.

In one embodiment, the non-peptidic agonist is selected from the group of 1-(p-thienylbenzyl)imidazole compounds, and preferably is Ave 0991 (i.e. 5-formyl-4-methoxy-2-phenyl-1[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole).

In one embodiment, the acute lung injury is an acute respiratory distress syndrome.

In one embodiment, the acute lung injury is related to a pulmonary (direct) or an extrapulmonary (indirect) lung injury.

In one embodiment, the pulmonary lung injury is selected from the group consisting of inhalation trauma, aspiration trauma, toxic lung oedema, lung infection, preferably pneumonia, lung contusion, and embolism.

In one embodiment, the extrapulmonary lung damage is associated with a disorder selected from the group consisting of sepsis, systemic inflammatory response syndrome (SIRS), polytrauma, shock, burn, acute pancreatitis, drug intoxication, alcohol abuse, chronic lung disease, mass transfusion, disseminated intravascular coagulation, erythema, and autoimmune lung disease.

In one embodiment, the subject is a mammal, preferably a human, most preferably an adult human.

The object of the present invention is further solved by a pharmaceutical composition comprising an Ang-(1-7) receptor agonist for use in the prevention and/or treatment of an acute lung injury in a subject.

The object of the present invention is further solved by a method for the prevention and/or treatment of an acute lung injury in a subject using a pharmaceutical composition comprising an Ang-(1-7) receptor agonist.

In one embodiment of the pharmaceutical composition, the Ang-(1-7) receptor agonist is a Mas receptor agonist.

In one embodiment of the pharmaceutical composition, the receptor agonist is a peptidic or non-peptidic agonist.

In one embodiment of the pharmaceutical composition, the peptidic agonist is an Ang-(1-7) peptide comprising an amino acid sequence according to SEQ ID NO: 1 or is a derivative or analogue thereof.

In one embodiment of the pharmaceutical composition, the peptidic agonist is a peptide comprising an amino acid sequence according to SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 4.

In one embodiment of the pharmaceutical composition, the peptidic agonist is a peptide comprising an amino acid sequence according to SEQ ID NO: 5 or is a derivative or analogue thereof.

In one embodiment of the pharmaceutical composition, the peptidic agonist is an Ang IV peptide comprising an amino acid sequence according to SEQ ID NO: 6 or is a derivative or analogue thereof.

In one embodiment of the pharmaceutical composition, the peptidic agonist is an Ang III peptide comprising an amino acid sequence according to SEQ ID NO: 7 or is a derivative or analogue thereof.

In one embodiment of the pharmaceutical composition, the non-peptidic agonist is selected from the group of 1-(p-thienylbenzyl)imidazole compounds, and preferably is Ave 0991 (i.e. 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole).

In one embodiment of the pharmaceutical composition, the acute lung injury is an acute respiratory distress syndrome.

In one embodiment of the pharmaceutical composition, the acute lung injury is related to a pulmonary (direct) or an extrapulmonary (indirect) lung injury.

In one embodiment of the pharmaceutical composition, the pulmonary lung injury is selected from the group consisting of inhalation trauma, aspiration trauma, toxic lung oedema, lung infection, preferably pneumonia, lung contusion, and embolism.

In one embodiment of the pharmaceutical composition, the extrapulmonary lung damage is associated with a disorder selected from the group consisting of sepsis, polytrauma, shock, burn, acute pancreatitis, drug intoxication, alcohol abuse, chronic lung disease, mass transfusion, disseminated intravascular coagulation, erythema, and autoimmune lung disease.

In one embodiment of the pharmaceutical composition, the subject is a mammal, preferably a human, most preferably an adult human.

In one embodiment, the pharmaceutical composition is formulated for a parenteral or enteral administration, preferably for a parenteral administration by the route of inhalation, infusion or injection. A pharmaceutical composition formulated for an oral, an intramuscular, an intravenous, a subcutaneous, a topical, a transdermal, a rectal, a vaginal, a pulmonary, an intranasal, an intrabuccal, or a sublingual administration is also considered.

In one embodiment, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, granules, a syrup, a spray, an aerosol, a liposomal composition, an ointment, a suppository, an implant, a plaster, or a slow release formulation.

In one embodiment, the pharmaceutical composition further comprises one or more pharmacologically inert and pharmaceutically acceptable excipients such as a polymer carrier, a disintegration agent, a lubricant, a solvent, or a swelling agent.

The term “receptor agonist” refers to an agent being capable of activating a receptor, i.e. eliciting a receptor response. The term “Ang-(1-7) receptor agonist” refers to an agent being capable of activating a receptor that is also activated by Ang-(1-7). The term “Mas receptor agonist” refers to an agent being capable of activating the G protein-coupled Mas receptor. As an adequate receptor response, a direct or indirect (due to a receptor physically interacting with Mas) G protein-mediated signalling cascade downstream from the receptor is initiated resulting in e.g. arachidonic acid release, PGI₂ formation, NO formation, and/or cGMP generation.

Since Ang-(1-7) signalling is blocked by A779 ([D-Ala⁷-Ang-(1-7); Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-D-Ala⁷, SEQ ID NO: 8) and/or D-Pro⁷-Ang-(1-7) (Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-D-Pro⁷, SEQ ID NO: 9), a further characteristic of an Ang-(1-7) agonist is the inhibition of its effects by A779 and/or D-Pro⁷-Ang-(1-7). Further non-competitive or competitive inhibitors are also considered.

The term “peptidic agonist” refers to a compound comprising one or more peptide bonds. The term encompasses compounds consisting of a pure peptidic structure, i.e. a peptide composed of two or more amino acids, as well as compounds comprising peptidic and non-peptidic structures.

The term “non-peptidic agonist” refers to a compound not comprising a peptide bond. Preferably, such a compound is of low molecular weight, i.e. a small molecule. The term “derivative” means a compound differing from another compound by a structural modification, for example by replacement of one atom or a group of atoms or a functional group with another atom or group of atoms or functional group.

The term “analogue” means a compound which is similar in structure or function to another compound.

The term “exogenous Ang-(I-7)” means Ang-(1-7) that is produced outside of the subject's body to be treated and is exogenously applied. This, however, does not exclude that Ang-(1-7) is produced in e.g. a transgenic animal not to be treated. Generally considered is Ang-(1-7) produced by biosynthesis or conventional lab synthesis, e.g. solid-phase synthesis.

The term “endogenous Ang-(1-7)” means that Ang-(1-7) is endogenously produced by the subject's body to be treated. An (increased) endogenous production of Ang-(1-7) can be the result of a stimulation of its generation from Ang II, e.g. by pharmacologically activating ACE2, by blocking the AT1a receptor, or by inhibiting the degradation of Ang II to Ang III by APA. Similarly, endogenous Ang-(1-7) production can be increased by stimulation of its generation from Ang I by NEP. An (increased) endogenous production can also be the result of a gene therapeutic intervention, e.g. by overexpressing ACE2 or a construct that generates directly Ang-(1-7) or one of its precursors. An increased concentration of endogenously produced Ang-(1-7) can also result from a reduced degradation of Ang-(1-7) e.g. by pharmacological inhibition of ACE which degrades Ang-(1-7) to Ang-(1-5).

Recombinant or overexpressed ACE2 will increase the concentration of Ang-(1-7) directly by stimulating its conversion from Ang II. ACE inhibitors will reduce Ang-(1-7) degradation to Ang-(1-5) while AT1a receptor blockers will increase Ang-(1-7) levels by elevation of ACE2 substrate availability.

Further considered are molecules, e.g. peptides or proteins, comprising the Ang-(1-7) peptide sequence or chemical structure.

“Acute lung injury” (ALI) and “acute respiratory distress syndrome” (ARDS) are inflammatory disorders of the lung most commonly caused by sepsis, pneumonia, trauma, and/or aspiration. Inflammation can be locally restricted to the lung, or the pulmonary inflammation can be part of a systemic inflammatory process. ALI and ARDS are characterized by hypoxemia and diffuse infiltrates on chest x-ray in the absence of elevated left atrial pressure. ALI and ARDS differ only in the degree of hypoxemia in that ALI is defined as a ratio of arterial oxygen partial pressure over inspiratory oxygen fraction (PaO₂/FiO₂)<300 and ARDS as a PaO₂/FiO2<200 (16). Diagnosis is by clinical presentation, ABGs (arterial blood gas analyses) and imaging studies. Treatment is with lung-protective, low tidal volume mechanical ventilation, supportive therapy, and treatment of underlying causes.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 shows the effects of Ang-(1-7) and the non-peptidic Ang-(1-7) receptor agonist AVE0991 on lung MPO activity (FIG. 1(A)), wet-to-dry weight ratio (FIG. 1(B)), mean arterial pressure (FIG. 1(C)) and pulmonary vascular resistance (FIG. 1(D)) in oleic acid induced acute lung injury. All data are mean±SEM from n=6 animals each; *p<0.05 vs. control; # p<0.05 vs. OA.

EXAMPLE

Animals.

Experiments were performed in male Sprague-Dawley rats (Charles River Wiga GmbH, Sulzfeld, Germany) with a body weight (bw) of 330-360 g. Animals received care in accordance with the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, 7th edition 1996). The study was approved by the local animal care and use committee.

Surgical Preparation and Hemodynamic Monitoring.

Rats were anesthetized by intraperitoneal injection of medetomidine (0.5 mg/kg bw, Domitor®, Dr. E. Graeub AG, Basel, Switzerland), fentanyl (0.05 mg/kg bw, JanssenCilag, Neuss, Germany) and midazolam (5 mg/kg bw, Dormicum®, Roche, Basel, Switzerland) as previously described (17). Following tracheotomy, the trachea was cannulated and ventilation was established (Advanced Animal Respirator, TSE Systems GmbH, Bad Homburg, Germany) with a tidal volume of 6 ml/kg bw at 80 breaths/min. Catheters (internal diameter 0.58 mm; Sims Portex Ltd., Hythe, United Kingdom) were introduced into the left carotid artery and the right internal jugular vein for monitoring of arterial blood pressure (AP), fluid replacement and drug delivery as previously described (18). An ultrasonic flowprobe (Transonic®, Transonic Systems Inc., Ithaca, N.Y.) was placed around the ascending aorta distal to the branching of the coronary arteries for continuous monitoring of cardiac output (CO). After median thoracotomy, a catheter was introduced via the right ventricle into the pulmonary artery for measurement of pulmonary artery pressure (PAP). AP, PAP and CO were continuously recorded by the software package DasyLab 32 (DasyLab, Moenchengladbach, Germany). Pulmonary vascular resistance (PVR) was calculated as arteriovenous pressure differences over flow under the assumption of a constant left atrial pressure of 2 mmHg.

Experimental Groups and Protocol.

Rats were randomly assigned to four groups of six animals each: Animals in group 1 (control) did not receive any pharmacological interventions. In group 2 (OA), ALI was induced by intravenous infusion of 0.2 mg/kg oleic acid (Sigma, Munich, Germany) over 30 min in the absence of any treatment. In group 3 (OA+Ang-(1-7)), ALI was induced as in group II, and infusion of Ang-(1-7) at 5 pmol/kg per min was initiated immediately after ALI induction. In group 4 (OA+AVE0991), ALI was induced as in group II, and infusion of AVE0991 at 500 pmol/kg per min was initiated immediately after ALI induction. In two additional groups of n=6 each, in which only myeloperoxidase (MPO) activity was measured, infusion of the Ang-(1-7) receptor blocker A779 (10 pmol/kg per min) was initiated either alone (group 5) or in combination with Ang-(1-7) (5 pmol/kg per min; group 6) immediately after induction of ALI.

After surgical preparation and hemodynamic stabilization over at least 15 min, baseline hemodynamics were recorded and arterial blood gases analyzed (RapidLab 348; Chiron Diagnostics GmbH, Fernwald, Germany). Removed blood volume was replaced by hydroxyethyl starch (6% hydroxyethyl starch 200/0.6; Fresenius, Bad Homburg, Germany). Immediately after baseline recordings, 0.2 mg/kg oleic acid was infused intravenously over 30 min in groups II-VI or an equal volume of 0.9% NaCl in group I. In all groups, measurements were repeated in 60 min intervals up to a total of 4 h at which time animals were sacrificed by exsanguination. After in situ ligation of the right main bronchus, lungs were excised and processed for determination of wet-to-dry weight ratio and myeloperoxidase (MPO) activity as described below.

Assessment of Lung Water and Inflammatory Response.

For determination of lung water content, wet-to-dry weight ratio was measured by use of the microwave drying technique (18). Recruitment of inflammatory cells was analyzed by measurements of MPO activity in lung homogenates as previously described (19). In brief, MPO activity was determined by a 3,3′-5,5′-tetramethylbenzidine (TMB)-based photometric assay, compared to appropriate standard curves, and expressed as units per gram lung tissue (U/g).

Statistical Analysis.

All data are presented as mean±SEM. Data were tested by Kruskal-Wallis test for differences between groups. Statistical significance was assumed at P<0.05.

Results.

Oleic acid induced ALI as characterized by an increase in MPO activity (FIG. 1(A)), lung wet-to-dry weight ratio (FIG. 1 (B)), and pulmonary vascular resistance (FIG. 1(D)), while systemic arterial pressure was reduced after 4 h as compared to control (FIG. 1(C)). Ang-(1-7) completely prevented the development of OA-induced ALI, as demonstrated by the fact that Ang-(1-7) infusion abrogated OA-induced changes in lung wet-to-dry weight ratio, MPO activity, and pulmonary vascular resistance. The protective effect of Ang-(1-7) was apparently not attributable to its described vasodilatory effect in systemic blood vessels, since Ang-(1-7) infusion attenuated systemic hypotension in OA-infused rats. The non-peptidic Ang-(1-7) receptor agonist AVE0991 similarly attenuated OA-induced ALI. Additional MPO analyses in groups 4 and 5 indicate that blockade of the Mas receptor by A779 aggravates OA-induced ALI, and blocks the rescue effect of Ang-(1-7) infusion.

Conclusions.

The present findings show that infusion of Ang-(1-7) or a non-peptidic Ang-(1-7) receptor agonist completely prevents lung oedema and inflammation in an experimental model of oleic-acid induced ALI. This protective effect is mediated via the G-protein coupled receptor Mas, since it is lost after Mas blockade by A779. Endogenously formed Ang-(1-7) serves as an intrinsic protection mechanism against ALI, which is aggravated after Mas blockade by A779.

REFERENCES

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1. An Ang-(1-7) receptor agonist for use in the prevention and/or treatment of an acute lung injury in a subject.
 2. The receptor agonist according to claim 1, wherein the receptor agonist is a Mas receptor agonist.
 3. The receptor agonist according to claim 1 or 2, wherein the receptor agonist is a peptidic or non-peptidic agonist.
 4. The receptor agonist according to claim 3, wherein the peptidic agonist is an exogenous or endogenous Ang-(1-7) peptide comprising an amino acid sequence according to SEQ ID NO: 1 or is a derivative or analogue thereof.
 5. The receptor agonist according to claim 3, wherein the peptidic agonist is a peptide comprising an amino acid sequence according to SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO:
 4. 6. The receptor agonist according to claim 3, wherein the peptidic agonist is an exogenous or endogenous NorAng-(1-7) peptide comprising an amino acid sequence according to SEQ ID NO: 5 or is a derivative or analogue thereof.
 7. The receptor agonist according to claim 3, wherein the peptidic agonist is an exogenous or endogenous Ang IV peptide comprising an amino acid sequence according to SEQ ID NO: 6 or is a derivative or analogue thereof.
 8. The receptor agonist according to claim 3, wherein the peptidic agonist is an exogenous or endogenous Ang III peptide comprising an amino acid sequence according to SEQ ID NO: 7 or is a derivative or analogue thereof.
 9. The receptor agonist according to claim 3, wherein the non-peptidic agonist is selected from the group of 1-(p-thienylbenzyl)imidazole compounds, preferably is Ave
 0991. 10. The receptor agonist according to any of claims 1 to 9, wherein the acute lung injury is an acute respiratory distress syndrome.
 11. The receptor agonist according to claims 1 to 10, wherein the acute lung injury is related to a pulmonary or an extrapulmonary lung injury. 